Abstract
Background/Aim: Hypofractionated radiation therapy is not commonly used in head and neck cancers (HNC) due to increased toxicity observed in historical cohorts. This study reviews our institutional experience using hypofractionated intensity modulated radiation therapy (H-IMRT) for HNC. Patients and Methods: A retrospective cohort study of 56 patients with HNC treated with H-IMRT with ≥50 Gy in 20 fractions was conducted. The primary outcomes were acute and late toxicity. Results: Two-year locoregional control was 87% and median overall survival was 46 months. There were no acute or late grade 4 or 5 toxicities. Acute grade 2 and 3 toxicity was seen in 79% (N=44) and 25% (N=14), respectively. Late grade 2 toxicity was seen in 9% (N=5). No patients required the placement of a feeding tube or tracheostomy. Conclusion: H-IMRT for the definitive or post-operative treatment of HNC using ≥50 Gy in 20 fractions appears safe and well tolerated with modest toxicity.
Head and neck cancers (HNC) are responsible for an estimated 4% of all cancers in the United States with approximately 14,500 deaths in 2020 (1). Standard radiation treatment for HNC includes conventionally fractionated intensity modulated radiation therapy (CF-IMRT), commonly 60-70 Gy at 1.8 to 2 Gy per fraction and can be associated with substantial acute and late side effects. Hypofractionated radiotherapy has been shown in many disease sites, including breast, prostate, and rectal cancer, to reduce overall treatment time with similar efficacy and toxicity to that of CF-IMRT (2–7). However, hypofractionated radiotherapy is not commonly used in HNC due to a concern for a higher risk of increased toxicity when increasing the dose per fraction to mucosal surfaces of the head and neck. Over the last two decades, dramatic reductions in acute and late toxicities have been made possible with the advent of advanced treatment planning such as intensity modulated radiation therapy (IMRT) and volumetric arc therapy (VMAT), allowing for improved sparing of non-target structures (8). As such, hypofractionated IMRT (H-IMRT) warrants re-evaluation in the modern treatment planning era for HNC.
H-IMRT is specifically worth studying in HNC as it can reduce many aspects of treatment burden associated with long treatment courses. Patients from geographically restricted areas or those with limited socioeconomic resources, challenges commonly faced by the United States HNC population, can particularly benefit from shorter treatment courses. H-IMRT can also be a substantial benefit for patients in low- and middle-income countries where patients often face long wait times and access to care can be difficult (9, 10). H-IMRT for HNC is currently implemented sparingly in few countries, most commonly in the United Kingdom (11–15). In the United States there is a paucity of literature evaluating this treatment paradigm.
There was minimal interest in H-IMRT for HNC in the United Stated until the COVID-19 pandemic forced physicians to critically evaluate conventionally fractionated radiotherapy treatment courses as a means to reducing the risk of transmission of COVID-19. This led to the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) consensus guideline which addresses the use of H-IMRT in early and late pandemic scenarios (16). Herein we report our institutional experience using H-IMRT for HNC, including clinical outcomes and associated toxicities.
Patients and Methods
This study is an institutional review board approved, single-institution retrospective analysis of patients with primary HNC, treated with definitive or post-operative H-IMRT from 2011 to 2020. Patients treated with ≥50 Gy in 20 fractions to the primary tumor site and/or neck were included, a subset of whom also received a secondary elective dose of 45-50 Gy in 20 fractions concurrently. VMAT or step-and-shoot IMRT with daily cone-beam CT image guidance was used in all patients. Exclusion criteria included treatment to a superficial target only without proximity to mucosal surfaces or coverage of the elective neck (e.g., scalp; skin only targets), a history of prior head and neck radiation, and <90 days follow up after completion of H-IMRT.
The primary outcomes of this study were acute and late toxicity. Secondary outcomes included locoregional control (LRC) and overall survival (OS). Toxicity was scored using CTCAE v4.0. Acute toxicity was defined as any event occurring during or ≤90 days after H-IMRT completion while late toxicity included any event occurring >90 days. In patients that developed a recurrence following treatment, toxicities that occurred following secondary treatment were not included. Multiple toxicities occurring in the same patient were scored separately. Descriptive statistics were used to describe demographics and toxicity outcomes. Kaplan Meier analysis was done to calculate LRC and OS estimates.
Results
Patient characteristics and treatment details. A total of 56 patients were treated with ≥50 Gy in 20 fractions with a median follow up of 12.8 months (range=3.1-93.3). Patient and disease characteristics are summarized in Table I. The majority of patients were Caucasian (94.6%) and male (78.6%) with a median age of 79 years (range=30-93). The most common primary tumor sites were skin (50%), major salivary gland (17.9%), and oral cavity (8.9%). The most common histologies included squamous cell carcinoma (66.1%) followed by thyroid malignancy (7.1%), and melanoma (5.4%).
Patient, disease and treatment characteristics.
H-IMRT was delivered post-operatively in 80.4% and as a definitive treatment in 19.6% of patients. The most common radiation dose was 50 Gy (53.6%) followed by 55 Gy (42.9%). In 64.3% of patients a secondary elective dose of 45-50 Gy was used. Most patients (62.5%) received treatment for a newly diagnosed HNC while 37.5% were treated for recurrence, either at the primary site or in the neck. Treatment site included primary tumor site/bed with unilateral neck in 53.6%, primary tumor site/bed with bilateral neck in 19.6%, primary tumor site/bed alone in 14.3%, unilateral neck in 7.1%, and bilateral neck in 5.4%. Feeding tube and tracheostomy were present in 10.7% and 5.4% of patients, respectively, prior to H-IMRT.
Toxicity. Acute toxicity is described in Table II. Acute grade 2 and 3 toxicities were reported in 78.6% and 25% of patients, respectively. There were no grade 4 or 5 acute toxicities reported. No patients required placement of a feeding tube or tracheostomy during or after H-IMRT. Late toxicity was reported in 8.9% of patients, including neck fibrosis in 3 patients (5.4%) and trismus, aspiration pneumonia, and osteoradionecrosis in 1 patient (1.8%) each. No patient experienced grade 3 or higher late toxicity.
Acute toxicities following hypofractionated intensity modulated radiation therapy.
Locoregional control and overall survival. Two-year locoregional control (LRC) was 87% (95% CI=75-98%) and median OS was 46 months. Local failure occurred in 2 patients (3.6%); 1 patient had a cutaneous squamous cell carcinoma and another had anaplastic thyroid cancer. Regional failure occurred in 3 patients (5.4%); primary tumors included squamous cell carcinoma of the skin, squamous cell carcinoma of the oral cavity and anaplastic thyroid cancer.
Discussion
H-IMRT is a standard regimen for the treatment of localized prostate, breast, melanoma, and rectal cancers, but in HNC its use has been limited due to increased toxicity in historical treatment cohorts (2–7, 17). We demonstrate that in the modern treatment era, H-IMRT is an effective treatment that is tolerated well without any grade 4 or 5 acute or late toxicities. The rates of acute grade 2 and 3 toxicity at 79% and 25%, respectively, are comparable to results observed with conventionally fractionated IMRT (Table II) (18, 19) and no patients required a feeding tube or tracheostomy as a result of treatment.
Hypofractionated radiotherapy for HNC has been best studied in the United Kingdom; however, few of these investigations included advanced treatment planning with IMRT and VMAT (11–13). Table III summarizes all published studies that have investigated H-IMRT. In 2020, the Princess Margaret Hospital group reported their experience treating HNC using H-IMRT alone versus accelerated RT versus conventionally fractionated chemoradiation; 15.9% of patients (N=324) received H-IMRT (15). They showed comparable 3-year LRC between H-IMRT, accelerated RT, and concurrent chemoradiation except for those with locally advanced human papilloma virus (HPV) negative disease. Acute toxicity was not reported, but at a median follow up of 4.8 years, late grade 3 and 4 toxicities were less common in the H-IMRT group compared to the concurrent chemoradiation group treated with conventional fractionation (HPV negative: 4% vs. 21%; p<0.001; HPV positive: 9% vs. 16%; p=0.03).
Studies investigating the efficacy and safety of hypofractionated intensity modulated radiation therapy to the head and neck.
In the United Kingdom PET NECK trial, patients with advanced head and neck squamous cell carcinoma underwent chemoradiation with 3D conformal RT or IMRT and were then randomized to planned neck dissection versus PET-CT surveillance; 11% of patients (N=56) received 55 Gy in 20 fractions (20). There were no statistically significant differences in primary local control, OS and quality of life at 2-year follow up between the hypofractionated and conventionally fractionated radiation cohorts (21). IMRT was utilized in 62.4% of patients (N=332). Importantly, patients treated with IMRT had improved quality of life compared to patients treated with 3D conformal RT.
In Brazil, Jacinto et al. demonstrated a favorable toxicity profile for 20 patients with stage III-IV HNC treated with 55 Gy in 20 fractions with IMRT and concurrent cisplatin. Four patients required a feeding tube at two months, while only 1 patient required a feeding tube by 1 year. Grade 3 mucositis and dermatitis were seen in 40% and 30% of patients, respectively (14).
H-IMRT has also been used as an intensification strategy to dose escalate patients in an effort to improve control. Meade et al. prospectively investigated 15 patients with oropharyngeal squamous cell carcinoma treated with 64 Gy in 25 fractions with concurrent cisplatin. During treatment, the majority of patients developed grade 3 mucositis and dysphagia, and nearly half of the patients developed grade 3 dermatitis (13). At the 3 month follow-up, grade 3 mucositis and skin toxicity resolved. Notable adverse events included 1 patient requiring a feeding tube at 3 months which resolved within 1 year, and 2 patients with grade 3 and 4 mucosal ulcerations, which subsequently healed.
Practice recommendations by ASTRO and ESTRO recognized H-IMRT as a reasonable treatment approach for HNC during the COVID-19 pandemic, but only considered routine implementation of H-IMRT if severe resource constraints occurred (16). There was also very little agreement for use of concurrent chemotherapy with H-IMRT, with the final agreement to restrict its use to RT prescriptions of ≤2.4 Gy per fraction. The ongoing IAEA multinational phase 3 randomized controlled HYPNO trial is assessing the effectiveness of 55 Gy in 20 fractions compared to 66 Gy in 33 fractions for the treatment of stage I-IV cancers of the oropharynx, hypopharynx, larynx, and oral cavity, underscoring the importance of this question worldwide in the IMRT era (22).
This study has several limitations. First, as an initial report of our experience, the relatively short median follow up of 13 months limits our ability to fully assess late toxicity. Secondly, while all patients had at least some mucosal exposure to IMRT, justifying their inclusion in this study, a larger study including more patients with primary mucosal HNC is needed to ensure these initial favorable results apply to these patients. The large majority of patients were treated post-operatively, so the applicability of this dose and fractionation of 50-55 Gy in 20 fractions to definitive mucosal HNC patients requires further investigation. Similarly, no patients received concurrent chemotherapy. Lastly, this is a heterogeneous study of HNC which limits its applicability of oncologic outcomes such as LRC. While we believe this initial report is timely and offers promising results of hypofractionation in HNC, the increasing utilization of H-IMRT at our institution, ongoing follow up of this cohort, and results of the HYPNO trial will help address many of these limitations in the future.
Conclusion
H-IMRT is associated with acceptable rates of acute and late toxicity particularly without the need for treatment related tracheostomy or a feeding tube. Prospective clinical trials of H-IMRT are justified to evaluate applicability in the post-operative and definitive settings, as well as with concurrent chemotherapy.
Acknowledgements
This study was supported by the Melvin Markey Discovery Fund at Cleveland Clinic.
Footnotes
Authors’ Contributions
Study conception and design was performed by Zachary S. Mayo, Shlomo A. Koyfman, and Shauna R. Campbell. Data collection was performed by Zachary S. Mayo, Evelyn O. Ilori, and Brian Matia. Analysis and Interpretation of results was performed by Zachary S. Mayo, Chandana A. Reddy, Shlomo A. Koyfman, and Shauna R. Campbell. Statistical analyses were performed by Chandana A. Reddy. All of the Authors contributed to the drafting and preparation of this manuscript. All of the Authors reviewed the results and approve of the final version.
Conflicts of Interest
None of the Authors have any financial disclosures relevant to this topic.
- Received February 11, 2022.
- Revision received February 23, 2022.
- Accepted February 24, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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